Mutations and Diseases

Five Major Diseases

1. SARS-CoV-2

2. Hypertension

3. Diabetic Mellitus(Type 2)

4.Hypertrophic Cardiomyopathy

5.SGA Cardiovascular Diseases

It is to be noted that ACE2 from extensive search doesn't have many cases of major mutations within itself that cause diseases, rather a majority of the problems come from it's expression patterns in relation to regulation by other genes. The DisGeNET database marks many of the possible genetic variations of ACE2 in relation to diseases to be mostly indicative biomarkers or altered expression. The reasoning in which possibly explains the lack of significant ACE2 mutations seems to be the fact that its small coding sequences are buffered by larger introns in which lessen the likelihood of a genetic mutation event occurring on vital regions of the genome. (51)

SARS-CoV-2(2019):

Several Population Missense Mutations found with higher affinity to S1Protein/Receptor binding

Tyr199Cys Missense Mutation Direct Link to Database
Gln60Arg Missense Mutation Direct Link to Database

(52), (53)

Hypertension:

SNVs present at various locations in relation to over vasoconstriction of multiple hypertensive diseases

Intron Variant A/T; Rs2106809 Direct Link to Database
Intron Variant T/A; C rs1978124 Direct Link to Database
Intron Variant C/T; rs2074192 Direct Link to Database
Splice region Variant C/T; rs2285666 Direct Link to Database
Intron Variant C/T; rs4240157 Direct Link to Database
Intron Variant A/G; rs4646188 Direct Link to Database

Diabetic Mellitus(Type 2):

Missense Variants and SNPs have been associated with T2D (54)

Pro389His Missense Mutation Direct Link to Database
Intron Variant A/G; rs4646188 Direct Link to Database

(55)

Hypertrophic Cardiomyopathy:

Intron Variants are seen to be associated with increased magnitude of the disease in males (56)

Intron Variant G/C Direct Link to Database
Intron variant A>C / A>G / A>T Direct Link to Database

(57)

SGA Cardiovascular diseases:

Evidence that ACE2 SNP in small for gestational age babies is linked to future cardiovascular illnesses

neonatal rs2074192 T Direct Link to Database

(58)

Clinical Details:

SARS-CoV-2 is a highly infectious virus part of the coronavirus family which has predominantly caused the continuing 2019 pandemic. The virus is spread through virus ridden droplets of infected person’s, and the most common symptoms are fever, cough, loss of taste/smell senses, and tiredness. Cases have had varying levels of severity and symptoms which in some people could appear as non-symptomatic and easy recovery, while others could be left on respirators and possibly succumb to infection progressions. Although research is still being done to see who is most at risk, most studies have suggested it is mostly immunocompromised adults, risk factor correlation has been found also with those with heart disease, diabetes, hypertension, and chronic kidney disease.

(59)

Molecular Mechanism:

The viruses themselves carry a single strand RNA coated by a spiked membrane. The infection process begins with the receptor binding domain of the S(spike) proteins binding onto the peptidase M2 domain of the Ace2 receptors located on the outside of a cell’s plasma membrane. The virus body is able to hijack TMPRSS2 protease for the use of conformational changes of the spike/receptor complex made. The S1 subunit of the S-protein is removed, leaving the S2 subunit of the S-protein free to begin fusion of the virus membrane and cell membrane for proper endocytosis. Once inside the cell, the virus’s coat is removed which allows the RNA to freely be translated into the cytoplasm. Pp1a and pp1ab proteins are initially produced and are used to develop the replication-transcription complex which survives in its own double membrane vesicle inside the cell. The complex continues to create structural and accessory proteins in order to proliferate viral bodies. Hijack of the cell is completed by the exocytosis of the newly synthesized virus in which continuously targets other cells.

(60)

Inheritance patterns:

SARS-CoV-2 isn’t inherited but was rather spread first as a zoonotic disease, suspected to have originated from bats or pangolins, and eventually infected humans. The disease cannot be passed on through generations, however it’s infectivity rate does make it possible to be easily spread. The research on SARS-CoV-2 is ever expanding, due to such large research there have been discovery of certain risk factors and genetic variations which could alter susceptibility. ACE2 SNP variations for example have been correlated to different likelihood of inheriting the disease, also it’s location on the X chromosome has correlated to increased susceptibility in men.

Treatments:

The severity of the symptoms of SARS-CoV-2 made emergency drug repurposing integral to save the lives of those infected. The most well-known treatments included Remedesivir, Lopinavir/Ritonavir, and infamously Hydroxy-Chloroquine. Each respectively targeted different stages of the virus’s life cycle, from causing nonsense mutations in viral translation to actively degrading proteins involved in virus maturation. Hydroxy-Chloroquine itself is studied to be able to stop viral movement in and out of a cell’s plasma membrane, but it is to be noted that clinical trial results on it’s effectiveness have correlated little benefit from it’s usage. Several other drugs are being studied for possibly being adequate candidates for treatment, those being: Faripiravir, Azithromycin, Ivermectin, Ribavirin, Immunoglobulin, Corticosteroids, Interferons, and Tocilizumab. As presented in the gene section, interferons may be a very promising way of inhibiting ACE2 receptors by disabling its binding domain.

(61)

Clinical Details:

Hypertensive disease refers to a group of diseases cause by hypertension, otherwise known as having high blood pressure. It is heavily categorized by scarring damage to blood vessel lining due to increased blood movement and vasoconstriction. Symptoms aren’t usually pronounced until very severe, symptoms of extreme cases are usually shortness of breath, nosebleeds, and at worst strokes.

(62)

Molecular Mechanism:

Hypertension is a very involved process which could involve a multitude of factors and pathways such as the Natriuretic peptide system, Endothelin pathway, and distinctly the Renin-Angiotensin-Aldosterone System. The Natriuretic peptide system is a pathway in which neurohormones cause vasoconstriction in the body for protection against heart related diseases and changes expression in the RAAS pathway. The Endothelin pathway is a vasoconstriction network in cells found in blood vessels in which is antagonized by vasodilating Nitric oxide and prostacyclin pathways. The main contributor to hypertension and the main study of this project is the importance of the RAAS pathway. The RAAS system functions to regulate blood pressure in the body by usage of vasoconstriction/vasodilation. In response to blood pressure fluctuation, non-active prorenin expressed in the kidney is cleaved to form renin. Renin’s activated form has the capability of binding to angiotensinogen produced by the liver in order to create Angiotensin. Angiotensin I in presence of ACE is converted into angiotensin II, which stimulates vasoconstriction and blood pressure by binding to AT1 receptors. Angiotensin II can also vasodilate by binding to AT2 receptors, however it’s vasoconstriction properties are usually more pronounced. In the presence of ACE2 however, angiotensin I & II can be converted to angiotensin 1-9, 1-7, or 1-5, in which have vasodilation properties opposite to angiotensin II when the binded products attach to MAS receptors. In terms of hypertension, downregulation of such molecules associated with vasodilation would eliminate controls on the RAAS system and lead to increasing levels of stress on the veins.

(37, 63, 64, 65, 66)

Inheritance patterns:

Hypertension does not have a well known inheritance pattern in most cases. Hypertension is shown to be persistent in some families though, usually offspring do maintain a risk of having it. Secondary hypertension could be predicted from family history of correlated diseases associated with it. In the very few rare cases known as essential hypertension, the occurrence of epigenetic events during reproduction may cause inheritable conditions of the disease which is still being studied.

(67)

Treatments:

A plethora of antihypertensives have been developed to mitigate the various causes of hypertension. Due to large possibilities of what could possibly be causing the hypertension, doctor’s assign a given hypertensive in which would best target particular pathways the patient’s ailment may best be associated to. The types of antihypertensives provided by the American Heart Association are as follows: Diuretics, Beta-blockers, ACE inhibitors, Angiotensin II receptor blockers, Calcium channel blockers, Alpha blockers, Alpha-2 Receptor Agonists, Combined alpha and beta blockers, Central agonists, Peripheral adrenergic inhibitors, and Vasodilators. In relation to the ACE2 pathways, ACE inhibitors and Angiotensin II receptor blockers are especially interesting treatments. In ACE inhibition the prevention of hypertension from vasoconstriction is achieved by ACE inhibitor introduction which competes against Angiotensin I for the ACE active site. Less interactions between ACE and Angiotensin I causes a reduction of Angiotensin II, excess Angiotensin I can be altered by ACE2 to produce proteins associated with vasodilation. Angiotensin II receptor blockers differ by competing with Angiotensin II for AT2R and AT1R receptors, leading to a lowered vasoconstriction response. ACE2 could also actively

process excess Angiotensin II for possible vasodilation activity.

(68, 69, 70)

Major Mutations

SARS-CoV-2

Hypertensive Disease (Hypertension)